Diphenylamine derivatives

ABSTRACT

DIPHENYLAMINES SIBSTITUTED BY HALOALKYLSULFONAMIDO GROUPS AND OPTIONALLY SUBSTITUTED BY OTHER GROUPS ON THE PHENYL RINGS. THESE COMPOUNDS AND THEIR SALTS ARE ACTIVE ANTI-MICROBIAL AGENTS AND SOME ARE USEFUL AS ANTI-INFLAMMATORY AGENTS, ANALGESICS AND HERBICIDES.

United States Patent OlfiC 3,755,665 Patented Aug. 28, 1973DIPHENYLAMINE DERIVATIVES George G. I. Moore, Birchwood, and JosephKenneth Harrington, Edina, Minn, assignors to Riker Laboratories, Inc.,Northridge, Calif. N Drawing. Continuation-impart of abandonedapplication Ser. No. 28,082, Apr. 13, 1970. Thisapplication June 13,1972, Ser. No. 262,302

Int. Cl. A61k 27/00 US. Cl. 424-321 Claims ABSTRACT OF THE DISCLOSUREDiphenylamines substituted by haloalkylsulfonamido groups and optionallysubstituted by other groups on the phenyl rings. These compounds andtheir salts are active anti-microbial agents and some are useful asanti-inflammatory agents, analgesics and herbicides.

This is a continuation-in-part of application Ser. No. 28,082, filedApr. 13, 1970, now abandoned.

This invention relates to diphenylamines substituted by ahaloalkylsulfonamido group, and optionally substituted by other groupson the phenyl rings and to salts thereof. These compounds are activeanti-microbial agents and some are also active as anti-inflammatoryagents, analgesics and herbicides.

It is an object of the invention to provide compounds for the control ofmicrobes, e.g., fungi and bacteria (both gram-positive andgram-negative).

It is another object of the invention to provide compounds which areanti-inflammatory agents.

It is another object of the invention to provide compounds which modifythe growth of plants, i.e., which prevent, alter, destroy or otherwiseaffect the growth of plants.

It is another object of the invention to provide compounds which act asanalgesics.

It is a further object of the invention to provide a method forcontrolling micro-organisms.

It is a further object of the invention to provide a method forcontrolling inflammation in mammalian tissue.

It is a further object of the invention to provide a method forcontrolling unwanted plants.

It is a further object of the invention to provide a method forcontrolling pain.

It is still another object of the invention to provide anti-microbialcompositions containing one or more haloalkylsulfonamido-substituteddiphenylamines as active ingredients therein.

It is still another object of the invention to provide anti-inflammatorycompositions containing one or more haloalkylsulfoamido-substituteddiphenylamines as active ingredients therein.

It is still another object of the invention to provide herbicidalcompositions containing one or more haloalkylsulfonamido-substituteddiphenylamines as active ingredients therein.

It is still another object of the invention to provide analgesiccompositions containing one or more haloalkylsulfonamido-substituteddiphenylamines as active ingredients therein.

Still other objects will be made apparent by the followingspecification.

class of compounds consisting of substituted diphenyl amine compounds ofthe formula:

Yu Yn wherein R is lower haloalkyl, R is hydrogen or a microbiologicallyor agriculturally acceptable cation, R is hydrogen or lower alkyl, Y andY are independently selected .from the group consisting of lower alkyl,lower alkoxy, lower haloalkyl, lower alkoxycarbonyl and halogen and nand n are independently zero, one or two.

The term lower when applied to substituent groups (radicals) of thisinvention, such as alkyl, alkoxy, alkoxycarbonyl and haloalkyl, refersto groups containing one to about four carbon atoms. When n is zero, thering adjacent to the perfluoroalkylsulfonamido group is unsubstitutedexcept for that group and the phenyl a-mine group shown in the formula.Similarly, when n is zero, the second ring is unsubstituted except forthe group shown in the formula and attached thereto through the aminenitrogen.

R can be perhaloalkyl or partially halogenated alkyl, and the halogenscan be mixed in either case. Such modification of the halogenated moietyR has not been found to remove anti-microbial activity of the compoundsof the invention, but it has been found to change other activities ofcompounds of the invention. The halogens present are preferably fluorineor chlorine, although bromine and iodine may also be present. It ispreferred that at least one halogen is bonded to the alpha carbon atomor at least two halogens are bonded to the beta carbon atom. Compoundswherein R is trifiuoromethyl are most preferred. Preferably, also, R ishydrogen.

A subgroup of the compounds which are preferred as activeanti-inflammatory agents are those in which n and n are both zero.Particularly preferred as anti-inflammatory agents are the compounds ofthe formula wherein R is hydrogen or a pharmaceutically acceptablecation, R and Y are as previously defined and n is 0-l.

The compounds of the invention which are in the acid form, i.e.compounds of Formula I in which R, is hydrogen, form salts i.e., whereinR is a pharmaceutically or microbiologically acceptable cation. Theseare generally metal, ammonium and organic amine salts and can beprepared by treating the acid form with a stoichiometrically equivalentamount of an appropriate base under mild conditions. Among the metalsalts of the invention are alkali metal (e.g., lithium, sodium andpotassium), alkaline earth metal (e.g., barium, calcium and magnesium)and heavy metal (e.g., zinc and iron) salts as well as other metal saltssuch as aluminum. Appropriate bases for use in preparing the metal saltsinclude metal oxides, hydroxides, carbonates, bicarbonates andalkoxides. Some salts are also prepared by cation exchange reactions (byreacting a salt of the invention with an organic or inorganic salt in acation exchange reaction). The organic amine salts include the salts ofalkylamines and aromatic amines, primary, secondary or tertiary. Theseand the ammonium salts can be prepared by reacting the acid form withthe appropriate organic base or ammonium hydroxide. The pharmaceuticallyacceptable salts are generally the alkali metal, alkaline earth,ammonium and amine salts. Preferred among the pharmaceuticallyacceptable salts are those in which R, is an amine cation.

Any of the salts of the types set out above are microbiologically andagriculturally acceptable, the one chosen depending upon the particularuse and upon the economics of the situation.

The salts of the invention are frequently formed by reacting theprecursors in aqueous solution. This solution can be evaporated toobtain the salt of the compound, usually as a dry powder. In some cases,it may be more convenient to use a non-aqueous solvent such as alcohols,acetone, etc. The resulting solution is then treated to remove thesolvent, for example by evaporation under reduced pressure. Since manyof the salts are water soluble, they are often used in the form ofaqueous solutions. Also, they can be used in making pharmaceuticalpreparations in the form of capsules for oral administration.

Due to the acidity of the hydrogen of the sulfonamido group of FormulaI, some of the compounds of Formula I (i.e. those in which R isperfiuorinated) are also catalysts for certain acid-catalyzedpolymerizations, e.g., polymerization of epoxides.

To produce the compounds of Formula I wherein R is hydrogen, anaminodiphenylamine is condensed with a halo-alkylsulfonyl halide oranhydride according to the following equation:

wherein R R Y, Y, n and n' are as previously defined and Z represents ahalogen atom, preferably chlorine or fluorine or the correspondingalkane sulfonate grouping OSO R Approximately equivalent amounts of thereactants are brought together at temperatures most often rangingbetween about and 150 C. If necessary or desirable, the reaction can becarried out in a pressure vessel. Preferably, but not necessarily, anacid acceptor such as the alkali or alkaline earth metal carbonates andbicarbonates or a tertiary amine such as pyridine, triethylamine or N,N-dimethylam'line is utilized. The amount of the acid acceptor can bevaried widely; however, a 10 mole percent excess of that amount of basesufficient to bind the liberated strong acid (HZ) is routinely employed.

The condensation is also usually conducted in the presence of anappropriate inert organic solvent. Typical solvents suitable for thispurpose are methylene chloride, chloroform, carbon tetrachloride,benzene, toluene, l,2-dimethoxyethane, bis (Z-methoxyethyDether,acetonitrile, nitromethane, N,N-dimethylformamide and the like.

After reaction is complete, the product mixture can be extracted with adilute aqueous base solution. The product, in the form of a salt whichis usually soluble in the aqueous layer, is precipitated therefrom byaddition of a mineral acid such as hydrochloric or sulfuric acid, andcollected by filtration. The compounds prepared according to theforegoing procedures are solids purified, in general, by columnchromatography, although sometimes, by recrystallization from aqueousalcohol, trichloroethylene, hexane, benzene-hexane mixtures and thelike.

Alternatively the product may be recovered by removal of the solvent invacuo, or by dilution with water, acidifi cation and filtration.

Suitable haloalkylsulfonyl halides and anhydrides for use as startingmaterials in these procedures are known to the art, for example thosedescribed in U.S. Pat. 2,732,398, in the Journal of the Chemical Society(London) 3058 (1960) and elsewhere.

The aminodiphenylamines used in producing the compounds of the inventionare described in the general chemical literature or can be easilyprepared from corresponding known nitrodiphenylamines by reduction or byother well-known synthetic techniques.

The 3-nitrodiphenylamines are generally prepared by one of the knownreaction sequences shown below, starting with prior art compounds:

it NHCCH:

K2003 Yn Yn' On, CuCl Br E 1 N0 NHCCH:

O {lea N NO 0 ll i'JCHa I? N N No,- N0

hydrolysis a n Y Y' (III) Alternatively the 3-bromonitrobenzene can bereacted with the aniline directly to form 3-nitrodiphenylarnines,although this is generally a less preferred method.

The 2- and 4-nitrodiphenylamines are generally prepared by one of theabove reaction sequences, or by reacting a corresponding 2- or4-chloronitrobenzene with an aminobenzene by one of the known reactionsequences shown below, again starting with prior art compounds:

Cl H N- KZCHS N02 I n Ya. N (ortho or OZN Oi p r o y) \X NaN 6 Y. Ya.

+ Y's (III) Aminodiphenylamines are readily prepared by the reduction ofthe corresponding nitrodiphenylamine. Usually this reduction has beencarried out using Raney nickel and hydrogen gas, but other commonreduction techniques are readily applicable.

The nitrodiphenylamines and aminodiphenylamines are difiicult to purifyand some even decompose on standing. In most instances partiallypurified nitrodiphenylamines and aminodiphenylamines have been reactedto obtain the products of the invention which are generally more easilypurified.

As noted previously, the compounds of the invention are as a classactive as anti-microbial agents, although some are more active thanothers. The anti-microbial activity has been determined by a variationof the original agar-plate diffusion method of Vincent and Vincent. Theculture media employed are designed to meet the minimum essentialrequirements for the growth of the various test organisms. They arebased on the synthetic glucosesalts medium of Davis and Mingioli(DG-agar).-The table below gives the medium used for each of the test(7) Candida albicans DGY 1 Strains isolated from dental caries in ratsor hamsters at the National Institute of Dental Health and grown in PFYor APT agar.

The tests are carried out quantitatively by placing 4 ,ul. aliquots of 1percent, 0.1 percent and 0.01 percent solution of the test chemicals on6.5 mm. paper discs to give 40, 4.0 and 0.4 g. per disc, respectively.

For the first part of the tests, in serum-free media, the same culturemedia are used as described above. For the second part of the tests, alltest organisms except number 5, are grown in PGY agar supplemented withpercent horse serum. Organism number 5 is grown in APT agar supplementedwith 10 percent horse serum in a desiccator in 10 percent CO in air. Theothers (1, 2, 3, 4, 6 and 7) are grown in air. Plates were incubated at30 C. for 24 hours for the bacteria and C. albicans and 48 hours for A.niger. The diameters of the zones of inhibition are measured, and log mwas plotted against X where m is the weight of test compound on the discin pg. and X is the diameter of the zone of inhibition in mm.

The culture media used in the foregoing tests are as follows:

Leading references to the method used are: Vincent, J. G., and Vincent,Helen W., Proc. Soc. Exptl. Biol. Med. 55:162-164, 1944, and Davis, B.D., and Mingioli, E. S., Jour. Bact. 662129-136, 1953.

Preferred anti-microbial agents of the invention include2,3-dimethyl-2-trifluoromethylsulfonamidodiphenylamine, 2,3-dichloro2'-trifluoromethylsulfonamidodiphenylamine,2-trifluoromethylsulfonamidodiphenylamine,2-difluoromethylsulfonamidodiphenylamine,5-chloro-Z-trifiuoromethylsulfonamidodiphenylamine,4'-chloro-2-trifluoromethylsulfonamidodiphenylamine,2-chloromethylsulfonamidodiphenylamine and5-chloro-2-trifluoromethylsulfonamido-Z'-ethoxycarbonyldiphenylamine.

6 These compounds are presently preferred because of their broaderspectrum of activity (affecting at least four of the test organisms) andhigher degree of activity. Such antimicrobial agents are usefulfordisinfecting and sterilizing medical and dental equipment as componentsof disinfecting solutions.

Many of the compounds of the present invention are also activeanti-inflammatory agents. The anti-inflammatory activity can beconveniently demonstrated using assays designed to test the ability ofthese compounds to antagonize the local edema which is a characteristicof the anti-inflammatory response (rat foot edema test) and to inhibitthe onset of the erythematous manifestation of inflammation (guinea pigerythema test).

The edema test is performed on adult female rats. One group of 10 ratsserves as non-medicated controls, while another group of 10 ratsreceives the test compound at various times prior to the induction ofthe edema, usually 15 minutes, one hour and/ or 18 hours. The testcompound is administered as a suspension in 4 percent aqueous solutionof acacia. Edema is induced by the plantar injection of 0.5 percentcarrageenin (0.1 ml./foot) into the right hind foot. The left hind footreceives a like volume of 0.9 percent saline solution. One hour later,the volume of each hind foot is determined plethysmographically. Theedema is expressed as the increase in the volume of the edemogeninjected foot (volume of the edemogen foot less the volume of the salinefoot). The percent inhibition is calculated by dividing the meanincrease in the edema of the edemogen foot of the medicated group by themean increase in the non-medicated group, multiplied by 100. An activedose is that giving a statistically significant inhibition of theinduced edema, usually about 30-35 percent inhibition.

The erythema test is performed on adult, albino guinea pigs of eithersex weighing 400-600 g. Hair is removed from the abdomen of the animalsby a depilatory mixture the afternoon of the day prior to the day onwhich they are to be used. One group of 5 animals serves as nonmedicatedcontrols, while another group of 5 receives the test compound 30 minutesprior to direct exposure to ultraviolet light. For induction oferythema, the animal is restrained on a small animal board. Threecircular sections (6.8 mm. in diameter) of the ventro-lateral abdominalarea of the animal are then exposed to a controlled amount ofultraviolet radiation. Two hours after exposure, the erythema is scored0-5 on the basis of its intensity and completeness (full or partialcircles). The maximal score per animal is 15. The percent inhibition iscalculated on the basis of the mean score for the medi-, cated groupversus the nonmedicated group. An active dose is taken to be that givinga statistically significant inhibition of the induced erythema, usually35-40 percent inhibition. Modifications of this test include variationin the time and method of drug administration.

Leading references to this method are:

(1) Wilhelmi, Schweiz. Med. Wschr. 79:557, 1949, and (2) Winder et al.,Arch. Int. Pharmacodyn 116:261,

Preferred compounds of the invention with respect to anti-inflammatoryactivity are:

2-trifiuoromethylsulfonamidodiphenylamine triethylammonium3-trifluoromethylsulfonamidodiphenylamine triethylammonium4-trifluoromethylsulfonamidodiphenylamine4-chloro-2-trifluoromethylsulfonamidodiphenylamine-methyl-3-trifluoromethylsulfonamidodiphenylamine triethylammonium3'-methyl-3-trifluoromethylsulfonamidodiphenylamine2-trifluoromethylsulfonamidomethyldiphenylamine triethylammonium2-methyl-5-trifluoromethylsulfonamidodiphenylamine The compounds arepreferably administered orally as anti-inflammatory agents but otherknown methods of administration are contemplated as well, e.g.dermatomucosally (for example dermally, rectally, and the like) andparenterally, for example by subcutaneous injection, intramuscularinjection, intravenous injection and the like. Ocular administration isals included. Dosages ordinarily fall within the range of about 1 to 500rug/kg. of body weight of the mammal to be treated although oral dosagesare not usually above 100 mg./kg. and injection dosages are not usuallyabove 50 mg./ kg. Suitable forms for oral administration include liquids(such as four percent acacia suspensions), tablets (which may containanhydrous lactose microcrystalline cellulose, modified starch, calciumstearate and talc, as well as other conventional compounding agentstogether with the active anti-inflammatory agent) and capsules. Suitablecarriers for topical application include creams, gels, tapes and thelike. Liquidl formulations, such as solutions or suspensions of theactive ingredient in inert carriers, are contemplated for dosage byinjection.

Various compounds of the invention have also been found by animal teststo be active analgesic agents.

The herbicidal activity of compounds of the invention has been evaluatedusing experimental plantings, and a number of compounds of the inventionhave been found to be active herbicides.

The following examples are given for the purpose of further illustratingthe procedures of the present invention, but are not intended, in anyway, to be limiting on the scope thereof. Thus, while the majority ofthe examples relate to perfiuoromethanesulfonamides, otherperfluorocarbon groups can be substituted in place thereof. Also,although the examples relate for the most part to compounds in the acidform (that is having a hydrogen atom bonded to the sulfonamidonitrogen), and a few to the triethylarnmonium salt, it is understoodthat the other salts of the invention are also easily prepared and arelikewise contemplated. Such salts, which have a cation bonded to thesulfonamido nitrogen, generally have the utility areas of thecorresponding acid-form compounds.

All melting points in the examples are uncorrected.

EXAMPLE 1 The method generally used for the preparation of the 2- and4-aminodiphenylamine precursors is illustrated in this example.

A mixture of 3-trifluoromethylaniline (80.5 g., 0.5 mole),2-chloronitrobenzene (74.0 g., 0.5 mole), sodium acetate (61.5 g., 0.75mole), copper powder g.), cuprous chloride (90.5 g.) and nitrobenzene(300 ml.) is heated at 200 C. for 22 hours. The thick green paste issteam distilled to remove some impurities, then the residue is extractedwith dichloromethane dried over magnesium sulfate, filtered and thesolvent removed in vacuo. The infrared spectrum of this oil isconsistent with the structure of desired2-nitro-3-trifluoromethyldiphenylamine. This product is reduced withRaney nickel suspended in ethanol and hydrogen gas. The reaction mixtureis filtered, the solvent is removed in vacuo and the product, Z-amino-3'-trifluoromethyldiphenylamine, is recrystallized from a benzene-hexanemixture to yield a solid, M.P. 75-80" C. The infrared spectrum of thissolid indicates that it is the desired product.

Example 2 This example describes the method generally used for thepreparation of the 3-aminodiphenylamine precursors.

In a round-bottomed flask is placed bromobenzene (172.8 g., 1.1 moles),3-nitroacetanilide (100 g., 0.555 mole), copper powder (5.0 g.),potassium iodide (2.5 g.), potassium carbonate (76.5 g., 0.55 mole) anda pinch of cuprous chloride. This mixture is stirred for 4 hours at 170C., then steam distilled to remove volatile impurities for one andone-half hours. The residue is extracted with dichloromethane. Thedichloromethane fraction is evaporated in vacuo to yield a dark oil.This oil is treated with a solution of ethanol (150 ml.), water (150ml.) and concentrated hydrochloric acid (150 ml.) and heated on a steambath for sixteen hours. This mixture is cooled to give a red solid whichis separated by filtration. Dilution of the filtrate with waterprecipitates an additional fraction of red solid. Recrystallization ofthis product from ethanol gives 3-anilinonitrobenzene, M.P. 106108 C.

Example 3 This example is illustrative of an alternative method for thesynthesis of the 3-aminodiphenylamines.

A mixture of 3-trifluoromethylacetanilide (40.8 g., 0.2 mole),3-bromonitrobenzene (42.5 g., 0.21 mole), potassium carbonate (27.7 g.,0.2 mole), copper powder (4 g.), potassium iodide (2 g.) and cuprouschloride (0.1 g.) is heated at 180 C. for 22 hour-s. The resultantmixture is steam-distilled to remove volatile impurities. The residue isheated with ethanol (250 ml.), water (100 ml.), and potassium hydroxide(28 g., 0.5 mole) for three hours. The mixture is then steam-distilled,and the residue extracted with methylene chloride, dried over magnesiumsulfate, filtered and the solvent removed in vacuo to give ayellow-brown product. The infrared spectrum of this product isconsistent with the structure of 3-trifluoromethyl-3-nitrodiphenylamine.This product is reduced with Raney nickel in ethanol and hydrogen gas.The reaction mixture is filtered, the solvent is removed in vacuo andthe product is column chromatographed on an activated silica to give anoil Whose infrared spectrum indicates it is3-trifluoron1ethyl-3-aminodiphenylamine.

Example 4 This example is illustrative of an alternative method for thesynthesis of the 2- and 4-aminodiphenylamines.

To a mixture of sodium hydride in mineral oil (9.28 g., 0.2 mole) at 52percent and hexamethylphosphoramide (100 ml.) is added slowly2,3-dichloroaniline (32.2 g., 0.2 mole) in hexamethylphosphoramide (50ml.) at 35 45 C. under a nitrogen atmosphere. Next 2-chloronitrobenzene(31.5 g., 0.2 mole) in hexamethylphosphoramide (50 ml.) is added to thereaction mixture. The mixture is heated to 130 C. and maintained therefor seventeen hours. The mixture is steam distilled to remove volatileimpurities, and extracted repeatedly with dichloromethane, the extractsare dried over magnesium sulfate, filtered and the solvent removed invacuo. The dark residue is digested in percent ethanol ml.), thenfiltered to give a dark powder. The infrared spectrum of this product isconsistent with the structure of 2,3-dichloro-Z'-nitrodiphenylamine,M.P. -120 C. This product, 14.4 g., 0.05 mole is slurried in methanol(100 ml.) and reduced with Raney nickel and hydrogen gas. The solvent isremoved in vacuo, and the infrared spectrum of the product indicates itis 2,3-dichloro-2'-aminodiphenylamine. The product is purified by columnchromatography on neutral alumina, being eluted rapidly withtrichloroethylene.

Example 5 The following are illustrative of the preparation of thecompounds of the invention.

Part of the product of Example 1, 2-amino-3-tritluoromethyldiphenylamine(25.2 g., 0.10 mole), and triethylamine (15 ml.) and dichloromethane arestirred and cooled to maintain the temperature below 20 C. while addingtrifluoromethanesulfonic anhydride (16.9 mL, 0.10 mole), then stirringis continued for one hour. The reaction mixture is washed with 10percent hydrochloric acid before removing the solvent (in vacuo) anddissolving the residue in 10 percent sodium hydroxide. This basicsolution is steam distilled to remove volatile impurities, then treatedwith decolorizing charcoal, and reacidified to give a reddishmateriaLThis material is extracted with chloroform, dried over magnesiumsulfate, filtered and the solvent removed in vacuo. The reddish solidresidue is thenchromatographed on, acid alumina. The early fractions,eluted with trichloroethylene, yield a tan solid when evaporated. Thissolid is recrystallized twice from a benzene-hexane mixture to yieldwhite needles of 3'-tn'fluoromethyl 2trifluoromethylsulfonamidodiphenylamine, M.P. 120-121 C.

Analysis.-Calcd. for C H F N O S (percent): C, 43.9; H, 2.6. Found(percent): C, 44.1; T, 2.8.

Example 6 Crude Z-methyl-3-trifluoromethylsulfonamidodiphenylamine (2.0g., 6.0 mole), prepared from the appropriate intermediate compoundsaccording to the procedure of Example 5 is dissolved in diethyl ether,the solution is filtered to remove solid impurities and excesstriethylamihe is added. The solvent and excess triethylamine are removedin vacuo, and the tan solid obtained is recrystallized twice from anisopropanolisopropyl ether mixture to give a tan power, triethylammonium2'-methyl-3-tri fluoromethylsulfonamidodiphenylamine, M.P. 108-110.5 C.

Analysis.Calcd. for C 5H F N S (percent): C, 55.7; H, 6.5; N, 9.7. Found(percent): C, 56.1; H, 6.5; N, 9.7.

Example 7 4-chloro-2-nitroaniline (100 g., 0.58 mole) in triethylamine(250 ml.) is reacted with trifluoromethanesulfonyl fluoride (88.5 g.,0.58 mole), in a pressure reactor at 90 C. for 20 hours. The solution ismade basic with concentrated sodium hydroxide solution, then steamdistilled. The residue is treated with decolorizing charcoal, filtered,then acidified with concentrated hydrochloric acid and extracted twicewith 250 ml. portions of chloroform. The extracts are dried overmagnesium sulfate, filtered and evaporated in vacuo to obtain product,4- chloro-Z-nitrotrifiuoromethanesulfonanilide. Part of this compound(20 g., 0.066 mole) is dissolved in ethanol, placed under a nitrogenatmosphere and treated with Raney nickel, then reduced under hydrogengas. The mixture is activated with sulfur, filtered and the filtrate isevaporated in vacuo. An infrared spectrum of the product is consistentwith the assigned structure, 2-amino-4-chlorotrifluoromethylsulfonanilide.

2 -amino-4-chlorotrifiuoromethylsulfonanilide (17.4 g., (0.063 mole) ismixed with potasium hydroxide solution (0.063 equivalent) and thesolution is evaporated in vacuo to give the potassium salt (19.2 g.,0.061 mole), which is placed in dimethylformamide (20 ml.) withpotassium 2-bromobenzoate (14.6 g., 0.061 mole), 'N-ethylmorpholine(7.05 g., 0.061 mole) and cupric bromide (1 g.) and heated at 145 C. for3.5 hours. The mixture is cooled and poured into water (500 ml.), and 10percent sodium hydroxide solution (75 ml.) is added. The mixture istreated with decolorizing charcoal, filtered and acidified withconcentrated hydrochloric acid. The solution is extracted withchloroform, dried over magnesium sulfate, filtered and evaporated invacuo. This purification is repeated, then the product is recrystallizedfrom toluene thrice. The product is-chloro-2-trifluoromethylsulfonamidodiphenylamine, M.P. 180.5-183" C.

5 chloro 2 trifluoromethylsulfonamidodiphenylamine (17.9 g., 0.045 mole)is esterified in ethanol (125 ml.) by heating at reflux temperature withhydrochloric acid (1 ml.) overnight, then adding sulfuric acid (2 ml.)and heating at reflux temperature for one day. The mixture is treatedwith decolorizing charcoal, filtered and evaporated to dryness in vacuo.The product is recrystallized from ethanol-water twice andbenzene-petroleum ether twice, then benzene once to give5-chloro-2-trifluoromethylsulfonamido-2'-(ethoxycarbonyl) diphenylamine,M.P. 114.5-116.5 C.

- the methods illustrated in th e foregoing examples.

Melting Example point No. Compound m C.)

8- 2-trlflu0romethylsulfonamldodlphenylamlue- 77. 5-79 9,3-d1methyl-2-trlfluoromethylsulfonamido- 76-78 dlphenylamine. 10 2,3-dleh1oro-2-trlfiuoromethylsulfonamldo- 70-725 dlphenylamlne. 11...4-chloro-Z-trlfluoromethylsulfonamtdodl- 121-122. 5

phenylamlne. 12 3-ehloro-Z-trifluoromethylsulfonamldodl- 112. 5-114.5

phenylamlne. 13 Trlethylammonium 2-ehloro-2-trlfluoro- 93-95. 5

methylstflfonamidodlphenylamine. 145-chloro-2-tnfluoromethylsulfonamidodl- 116. 5-117.5

phenylamine. 15 2-(trifluoromethylsulfonamldo)methyldi- 72-75phenylamlne. 16 -ch1oromethylsulfonamldodlphenylaminm.. 106. 5-108 172-fluoromethylsulfonamidodlphenylamine- 93.5-95.5 182-perfiuorobutylsulfonamldodiphenylamine. 70-71.5 19Z-dlfluoromethylsulfouamldodiphenylamine. 58-60 20 Trlethylammonlum3-trlfluoromethylsulfon- 106-110 amldodiphenylamine. 21 Triethylammonium4-tiifiuoromethylsulfon- 98-111 amidodlphenylamine. 223'trifiuoromethyl-B-trifluoromethylsulfon- 103. 5-105. 5

amidodiphenylamine. 23. 2, 3-dlmethyl-T-trlfluoromethylsulfonamldo-95-96. 5

dlphenylamine. 24 4'-methyl-3-trifiuoromethylsulfonamido- -82diphenylamine. 25 Triethylammonlum 3-methyl-3-trlfluoro- 91-93methylsulfonamldodlphenylamlne. 26 Trlethylammonlum Z-methyldtrlfiuoro-1 117-120 methylsuliouamidodiphenylamine.

1 Decomposes.

What is claimed 1s: 1. A method for combattrng inflammatory processes ina mammalian animal which comprises administering to said animal a doseeffective for the control of the inflammatory processes but less thanthe toxic amount of a compound of the formula:

CFsSOzIIT I R I II I:

wherein R is hydrogen or triethyl ammonium, R is hydrogen or loweralkyl, Y is lower alkyl, or halogen and n' is 0 or 1.

2. A methyl according to claim 1 wherein n is 0.

3. A method according to claim 1 wherein R is hydrogen.

4. A method according to claim 1 wherein the compound is2-trifluoromethylsulfonamidodiphenylamine.

5. A method according to claim 1 wherein the compound istriethylammonium 3-trifluoromethylsulfonamidodiphenylamine.

6. A method according to claim 1 wherein the compound istriethylammonium 4-trifluoromethylsulfonamidodiphenylamine.

7. A method according to claim 1 wherein the compound is4'-chloro-2-trifluoromethylsulfonamidodiphenylamine.

8. A method according to claim 1 wherein the compound is4-methyl-3-trifiuoromethylsulfonamidodiphenylamine.

9. A method according to claim 1 wherein the compound istriethylammonium 3'-methyl-3-trifiuoromethylsulfonamidodiphenylamine.

10. A method according to claim 1 wherein the com- 11 112 pound is 2trifluoromethylsulfonamidomethyldiphenyl- FOREIGN PATENTS amine. r I y6,4 1

References Cited T 3 1 UNITED STATES PATENTS STANLEY J. FRIEDMAN,--Primapy' Examiner n 7, 7 1 72 ersger 424-321 C1; XRb 3,661,990 5/1972Harrington 424-321 v 1 I i I 3,689,553 9/1972 Moore et a1. 424-321 IQ Fv UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,7555 Dated August 28. 1973 I ven flfl) Geor e G.I. Moore anci JosephKenneth Havr'ingi-nn It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Column 1, line 17, following "are" insert --also--- Column 3, line 30.,

-- R, I a i N NH +R 2 SO Z-9 l II II Column 9, llne l0, C H F N O Sshould be -C H F N O S-'- Column 9, line 11, "T," should be --H,-

Column 9, line 1 4, "2-" should be -2' Column 9, line 44, "activated"should be --deactivated-- Column l0, line 55, "methyl" should be--method-- Signed and sealed this nth day of June 197k (SEAL) Attest:

EDWARD M.FLETCI-ER,J'R. C. MARSHALL DANN Att'esting Officer Commissionerof Patents

